The ketogenic diet (KD) is a high-fat, low-carbohydrate and low-protein diet designed to mimic the metabolic and biochemical changes seen during fasting (prominently, ketosis). The KD is remarkably effective in the treatment of medically refractory epilepsy but the underlying mechanism(s) have not been elucidated. Interestingly, in addition to proven anticonvulsant properties, there is growing evidence that the KD may enhance cognitive functioning in epileptic patients. Given the rising concern for neurobehavioral problems associated with intractable epilepsy, and the expanding recognition that anticonvulsant drugs can themselves impair cognition, there is an urgent need to develop novel interventional strategies. Ketone bodies have recently been shown to exert neuroprotective activity in several models of neurological disease. Similarly, we have shown that ketone bodies alone can reduce reactive oxygen species (ROS) formation in neocortex and prevent oxidative impairment of hippocampal long- term potentiation (LTP) in rats. Accordingly, we hypothesize that the functional neuroprotective properties of the KD-defined herein as anticonvulsant and/or nootropic-might be in part a direct consequence of ketone body action, specifically via ketone-mediated inhibition of a novel epileptic target, the mitochondrial permeability transition (mPT) complex. The fundamental goals of the proposed studies are to: (1) determine whether acute and chronic administration of ketone bodies can enhance cognitive function and preserve hippocampal LTP in epileptic mice; and (2) to demonstrate that the underlying molecular mechanism of action accounting for this beneficial effect is alteration of mPT. First, we propose to demonstrate that ketone body administration alone is sufficient to render functional neuroprotective effects in epileptic mice. Next, we hope to demonstrate that the pharmacological inhibition of the mPT complex- specifically through an interaction with the cyclophilin D binding site-is responsible for the neuroprotective effects of ketone bodies. For the proposed studies, we will employ standard video-EEG and cellular electrophysiological techniques, behavioral tests of spatial learning/memory function, and mitochondrial biochemical assays. The results of our investigations may lead to an improved understanding of the mechanisms underlying the functional neuroprotective effects of the KD in epileptic brain, and may provide novel avenues for future therapies for intractable epilepsy and for important related co-morbidities such as cognitive dysfunction - an area that is a current NINDS Benchmark for Epilepsy Research. PUBLIC HEALTH RELEVANCE: Patients with epilepsy often suffer from cognitive and mood difficulties, and there are currently no effective therapies to treat these problems. There is growing scientific evidence that ketone bodies, produced by the liver in response to a special anticonvulsant diet, possess functional neuroprotective properties and may be helpful in countering cognitive dysfunction as well as seizure activity. This proposal will explore a potential molecular mechanism through which ketone bodies might exert such effects.